title: Abelson tyrosine kinase facilitates Salmonella enterica serovar Typhimurium entry into epithelial cells.
abstract: The intracellular gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium gains entry into nonphagocytic cells by manipulating the assembly of the host actin cytoskeleton. S. enterica serovar Typhimurium entry requires a functional type III secretion system, a conduit through which bacterial effector proteins are directly translocated into the host cytosol. We and others have previously reported the enhancement of tyrosine kinase activities during Salmonella serovar Typhimurium infection; however, neither specific kinases nor their targets have been well characterized. In this study, we investigated the roles of the cellular Abelson tyrosine kinase (c-Abl) and the related protein Arg in the context of serovar Typhimurium infection. We found that bacterial internalization was inhibited by more than 70% in cells lacking both c-Abl and Arg and that treatment of wild-type cells with a pharmaceutical inhibitor of the c-Abl kinase, STI571 (imatinib), reduced serovar Typhimurium invasion efficiency to a similar extent. Bacterial infection led to enhanced phosphorylation of two previously identified c-Abl substrates, the adaptor protein CT10 regulator of kinase (CrkII) and the Abelson-interacting protein Abi1, a component of the WAVE2 complex. Furthermore, overexpression of the nonphosphorylatable form of CrkII resulted in decreased invasion. Taken together, these findings indicate that c-Abl is activated during S. enterica serovar Typhimurium infection and that its phosphorylation of multiple downstream targets is functionally important in bacterial internalization.
authors.affiliation: Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908-0732, USA.
authors.forename: Kim Thien
authors.initials: KT
authors.lastname: Ly
authors.forename: James E
authors.initials: JE
authors.lastname: Casanova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001549:Benzamides; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012485:Salmonella typhi / Q000472:pathogenicity*
chemical_list: C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D003598:Cytoskeletal Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl